QSAR and DFT Studies of Some Tacrine-Hydroxamate Derivatives as Inhibitors of Cholinesterase (AChEs) in the Treatment of Alzheimer's Disease

Introduction: This work was devoted to an in silico investigation conducted on twenty-eight Tacrine-hydroxamate derivatives as a potential treatment for Alzheimer's disease using DFT and QSAR modeling techniques. Method(s): The data set was randomly partitioned into a training set (22 compounds) and a test set (6 compounds). Then, fourteen models were built and were used to compute the predicted pIC50 of compounds belonging to the test set. Result(s): Al built models were individualy validated using both internal and external validation methods, including the Y-Randomization test and Golbraikh and Tropsha's model acceptance criteria. Then, one model was selected for its higher R2, R2test, and Q2cv values (R2 = 0.768, R2adj = 0.713, MSE = 0.304, R2test=0.973, Q2cv = 0.615). From these outcomes, the activity of the studied compounds toward the main protease of Cholinesterase (AChEs) seems to be influenced by 4 descriptors, i.e., the total dipole moment of the molecule (mu), number of rotatable bonds (RB), molecular topology radius (MTR) and molecular topology polar surface area (MTPSA). The effect of these descriptors on the activity was studied, in particular, the increase in the total dipole moment and the topological radius of the molecule and the reduction of the rotatable bond and topology polar surface area increase the activity. Conclusion(s): Some newly designed compounds with higher AChEs inhibitory activity have been designed based on the best-proposed QSAR model. In addition, ADMET pharmacokinetic properties were carried out for the proposed compounds, the toxicity results indicate that 7 molecules are nontoxic.Copyright © 2023 Bentham Science Publishers.

Nanopore single-molecule analysis of biomarkers: Providing possible clues to disease diagnosis

Biomarker detection has attracted increasing interest in recent years due to the minimally or non-invasive sampling process. Single entity analysis of biomarkers is expected to provide real-time and accurate biological information for early disease diagnosis and prognosis, which is critical to the effective disease treatment and is also important in personalized medicine. As an innovative single entity analysis method, nanopore sensing is a pioneering single-molecule detection technique that is widely used in analytical bioanalytical fields. In this review, we overview the recent progress of nanopore biomarker detection as new approaches to disease diagnosis. In highlighted studies, nanopore was focusing on detecting biomarkers of different categories of communicable and noncommunicable diseases, such as pandemic COVID-19, AIDS, cancers, neurologic diseases, etc. Various sensitive and selective nanopore detecting strategies for different types of biomarkers are summarized. In addition, the challenges, opportunities, and direction for future development of nanopore-based biomarker sensors are also discussed.Copyright © 2023 Elsevier B.V.

A Review on Therapeutic Potential of Indian Herbal Plants to Counter Viral Infection and Disease Pathogenesis

Herbal plant extracts or purified phytocomponents have been extensively used to treat several diseases since ancient times. The Indian Ayurvedic system and Chinese traditional medicines have documented the medicinal properties of important herbs. In Ayurveda, the polyherbal formulation is known to exhibit better therapeutic efficacy compared to a single herb. This review focuses on six key ayurvedic herbal plants namely, Tinospora cordifolia, Withania somnifera, Glycyrrhiza glabra/Licorice, Zingiber officinale, Emblica officinalis and Ocimum sanctum. These plants possess specific phytocomponents that aid them in fighting infections and keeping body healthy and stress-free. Plants were selected due to their reported antimicrobial and anti-inflammatory effects in several diseases and effectiveness in controlling viral pathogenesis. An ad-vanced literature search was carried out using Pubmed and google scholar. Result(s): These medicinal plants are known to exhibit several protective features against various diseases or infections. Here we have particularly emphasized on antioxidant, anti-inflammatory, anti-microbial and immunomodulatory properties which are common in these six plants. Recent literature analysis has revealed Ashwagandha to be protective for Covid-19 too. The formulation from such herbs can exhibit synergism and hence better effectiveness against infection and related dis-eases. The importance of these medicinal herbs becomes highly prominent as it maintains the har-monious balance by way of boosting the immunity in a human body. Further, greater mechanistic analyses are required to prove their efficacy in fighting infectious diseases like Covid-19. It opens the arena for in-depth research of identifying and isolating the active components from these herbs and evaluating their potency to inhibit viral infections as polyherbal formulations.Copyright © 2023 Bentham Science Publishers.

Novel Organoruthenium(II) Complex C1 Selectively Inhibits Butyrylcholinesterase without Side Effects on Neuromuscular Transmission.

Enzyme butyrylcholinesterase (BChE) shows increased activity in some brain regions after progression of Alzheimer's disease and is therefore one of the therapeutic targets for symptomatic treatment of this neurodegenerative disorder. The organoruthenium(II) complex [(η6-p-cymene)Ru(II)(1-hydroxy-3-methoxypyridine-2(1H)-thionato)pta]PF6 (C1) was designed based on the results of our previous structure-activity studies. Inhibitory activity toward cholinesterase enzymes shows that this complex selectively, competitively, and reversibly inhibits horse serum BChE (hsBChE) with an IC50 value of 2.88 µM. When tested at supra-pharmacological concentrations (30, 60, 90, and 120 µM), C1 had no significant effect on the maximal amplitude of nerve-evoked and directly elicited single-twitch and tetanic contractions. At the highest tested concentration (120 µM), C1 had no effect on resting membrane potential, but significantly decreased the amplitude of miniature end-plate potentials (MEPP) without reducing their frequency. The same concentration of C1 had no effect on the amplitude of end-plate potentials (EPP), however it shortened the half-decay time of MEPPs and EPPs. The decrease in the amplitude of MEPPs and shortening of the half-decay time of MEPPs and EPPs suggest a possible weak inhibitory effect on muscle-type nicotinic acetylcholine receptors (nAChR). These combined results show that, when applied at supra-pharmacological concentrations up to 120 µM, C1 does not importantly affect the physiology of neuromuscular transmission and skeletal muscle contraction.

A Novel Multifunctional 5,6-Dimethoxy-Indanone-Chalcone-Carbamate Hybrids Alleviates Cognitive Decline in Alzheimer's Disease by Dual Inhibition of Acetylcholinesterase and Inflammation.

Backgrounds: Alzheimer's disease (AD) is a multifactorial neurodegenerative disease. The treatment of AD through multiple pathological targets may generate therapeutic efficacy better. The multifunctional molecules that simultaneously hit several pathological targets have been of great interest in the intervention of AD. Methods: Here, we combined the chalcone scaffold with carbamate moiety and 5,6-dimethoxy-indanone moiety to generate a novel multi-target-directed ligand (MTDL) molecule (E)-3-((5,6-dimethoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)-methyl)phenylethyl(methyl) carbamate (named AP5). In silico approaches were used to virtually predict the binding interaction of AP5 with AChE, the drug-likeness, and BBB penetrance, and later validated by evaluation of pharmacokinetics (PK) in vivo by LC-MS/MS. Moreover, studies were conducted to examine the potential of AP5 for inhibiting AChE and AChE-induced amyloid-ß (Aß) aggregation, attenuating neuroinflammation, and providing neuroprotection in the APP/PS1 model of AD. Results: We found that AP5 can simultaneously bind to the peripheral and catalytic sites of AChE by molecular docking. AP5 exhibited desirable pharmacokinetic (PK) characteristics including oral bioavailability (67.2%), >10% brain penetrance, and favorable drug-likeness. AP5 inhibited AChE activity and AChE-induced Aß aggregation in vivo and in vitro. Further, AP5 lowered Aß plaque deposition and insoluble Aß levels in APP/PS1 mice. Moreover, AP5 exerted anti-inflammatory responses by switching microglia to a disease-associated microglia (DAM) phenotype and preventing A1 astrocytes formation. The phagocytic activity of microglial cells to Aß was recovered upon AP5 treatment. Importantly, chronic AP5 treatment significantly prevented neuronal and synaptic damage and memory deficits in AD mice. Conclusion: Together, our work demonstrated that AP5 inhibited the AChE activity, decreased Aß plaque deposition by interfering Aß aggregation and promoting microglial Aß phagocytosis, and suppressed inflammation, thereby rescuing neuronal and synaptic damage and relieving cognitive decline. Thus, AP5 can be a new promising candidate for the treatment of AD.

LUNG TRANSPLANTATION IN THE UNITED STATES: COMPARISON OF SOCIODEMOGRAPHIC TRENDS BETWEEN 2001 AND 2021

SESSION TITLE: Lung Transplantation: New Issues in 2022 SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: This population-based study describes the changing demographic trends of Lung Transplants (LT) across the United States (U.S.) over the last two decades (2001 vs 2021). METHODS: We utilized the Organ Procurement and Transplantation Network (OPTN) registry to gather data on LT recipients across the U.S. for the year 2001 and 2021. Total yearly lung transplant numbers were recorded from 1988 to 2021. The recipients were categorized into subgroups based on age (<1, 1-5, 6-10, 11-17, 18-49, 50-64 and >65 years), race (Whites, Blacks, Hispanic/Latino, Asians, and Others) and most common diagnosis, and data was tabulated to compare for the years 2001 and 2021. RESULTS: From 1988 to 2021, 46,109 LTs were performed in the U.S. The yearly LT recipients increased from 1,059 in 2001 to 2,524 in 2021. The most common reason for LT was Emphysema/COPD (Chronic Obstructive Pulmonary Disease) in 2001 (n=464) and IPF (Idiopathic Pulmonary Fibrosis) in 2021 (n=899). In both 2001 and 2021, most LT recipients were in the age group 50-64 years (45.8% vs 58.1%) but the proportion of patients > 65 years receiving LT increased noticeably from 3.4% in 2001 to 36.9% 2021. Most LT recipients in both 2001 vs 2021, had “O” blood group (~ 45%). White patients comprised the majority of those registered for and those who underwent LT in both 2001 (n=940;88.80%) and 2021 (n=1,778;70.40%), although the relative percentage reduced by 18.40%. The relative percentages for Blacks, Asians, Hispanics receiving LTs increased from 2001 to 2021 by 2%, 3.3% and 11.8% respectively. In both 2001 and 2021, the states where maximum LTs were performed included– California (10.8% vs 12.6%), Pennsylvania (9.6% vs 9.3%) and Texas (7.3% vs 10.7%) while the states with the least LTs included– Connecticut, Mississippi, Oregon. CONCLUSIONS: There has been a general uptrend in the total number of LTs year-on-year, and the likely drop in LT recipients in 2020 and 2021 was due to the COVID-19 pandemic. The most common diagnosis for transplant changed from Emphysema/COPD in 2001 to IPF in 2021. There are appreciable racial and geographical disparities in receiving LTs in the United States but there are encouraging improvements in 2021 compared to 2001. There is an increasing trend of LTs in elderly patients (> 65 years), likely due to increased supportive care and improved life expectancy. CLINICAL IMPLICATIONS: Changes in socio-demographic trends in lung transplant recipients help us understand existing disparities and access to advanced lung disease centers so that we can better address these with equitable healthcare delivery tailored to changing transplant trends. DISCLOSURES: No relevant relationships by FNU Amisha No relevant relationships by Perminder Gulani No relevant relationships by Manuel Hache Marliere No relevant relationships by paras malik No relevant relationships by Divya Reddy

IMPACT OF INHALED CORTICOSTEROID USE ON OUTCOMES IN HOSPITALIZED PATIENTS WITH COVID-19 AND OBSTRUCTIVE LUNG DISEASES

SESSION TITLE: COPD Medications and Treatment Outcomes SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Conclusive data on whether inhaled corticosteroids (ICS) have a protective effect on COVID-19 hospitalization rates or outcomes are lacking. The main objective of our study was to assess the impact of pre-hospitalization ICS use on the clinical course of hospitalized COVID-19 patients with underlying obstructive lung diseases - asthma and chronic obstructive pulmonary disease (COPD). METHODS: We conducted a retrospective chart review study of all COVID-19 patients hospitalized at our institution between March 1st - June 3th, 2020. Diagnosis of asthma and COPD was determined using ICD-10 codes. Demographics, information about pre-hospitalization ICS use and clinical data were recorded through chart review. Outcomes of interest were all-cause 28-day mortality and need for intubation. Chi-square or Fischer’s exact test was used to assess univariate associations. Linear and logistic regression models were constructed to adjust for potential confounders. RESULTS: Data was analyzed from 356 hospitalized COVID-19 patients with prior diagnosis of obstructive lung disease;219/356 (62%) had asthma, 137/356 (38%) had COPD. Hospitalized COVID-19 patients with asthma were younger (mean age 61 [range: 51-71] vs 74 [range:67-81] years, p<0.01), more likely to be female (69% vs 48%, p<0.01), Hispanic (43% vs 25%, p<0.01) and never smokers (52% vs 20%, p<0.01) compared to those with COPD. There was no difference in the use of pre-hospitalization ICS between the two groups (35.2% in Asthma vs 38% in COPD, p=0.59). Overall, COVID-19 patients with COPD were more likely to die compared to those with asthma (47% vs 25%, p<0.01). Pre-hospitalization ICS use was not significantly associated with all-cause 28-day mortality (asthma: OR 0.9 [95%CI 0.4-2.0], p=0.85;COPD: OR 0.7 [95%CI 0.3-1.5], p=0.3) or need for intubation (asthma: OR 1.0 [95%CI 0.5-2.0], p=0.94;COPD: OR 0.7 [95%CI 0.3-1.7],p=041) after adjusting for potential confounders. CONCLUSIONS: Mortality among hospitalized COVID-19 patients with COPD was higher compared to those with asthma. While the pre-hospitalization use of ICS was similar between the two groups, it did not protect hospitalized COVID-19 patients in either group from intubation or mortality. High mortality rates among COVID-19 patients with COPD is likely due to concomitant risk factors such as older age, and comorbidities such as diabetes and chronic kidney disease. Being a retrospective study, the quality of our data was limited and dependent on documentation accuracy. CLINICAL IMPLICATIONS: Pre-hospitalization ICS use did not improve outcomes in hospitalized COVID-19 patients with asthma or COPD. Further studies are required to investigate the role of ICS in preventing COVID-19 related hospitalizations, morbidity and mortality in randomized control settings. DISCLOSURES: No relevant relationships by Hammad Aleem No relevant relationships by Denisa Ferastraoaru No relevant relationships by Manuel Hache Marliere No relevant relationships by Gabriel Hernández Romero No relevant relationships by Christa McPhee No relevant relationships by Francine Palmares No relevant relationships by Divya Reddy No relevant relationships by Felix Reyes No relevant relationships by Deborah Schwartz

POSITIVE END-EXPIRATORY PRESSURE (PEEP) INDEX: A NOVEL, BETTER DISCRIMINATION MARKER THAN PAO2/FIO2 FOR RESCUE MEASURES IN COVID-RELATED ARDS

SESSION TITLE: ECMO and ARDS in COVID-19 Infections SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: COVID-related acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality. PaO2/Fio2 (PFR) is a prognostic and severity marker for ARDS. Other markers have been posited for ARDS. PEEP Index (PIx) [PEEP/PFR] or [(PEEP*Fio2)/PaO2] could serve as a new discriminatory marker to assess rescue therapies such as proning or ECMO referral. METHODS: Retrospective cohort study of all intubated COVID-19 patients with ARDS hospitalized at our institution between February 5th – May 11th, 2020. ARDS were calculated within first 24 hours of worst PaO2/FIO2 and their associated PEEP with bilateral infiltrates on Chest X-ray manually confirmed within 24hours of intubation fulfilling 2012 Berlin criteria. Outcomes of interest were all-cause in-hospital mortality, need for pronation and paralysis use. Binomial logistic regression with ROC curve were performed for univariate association for outcomes of interest. Cox proportional hazard regression modeling was performed and adjusted for potential confounders. PFR was transformed into a denominator of itself to reflect a direct proportional relationship. RESULTS: Data was analyzed from 113 hospitalized COVID-19 patients with identified ARDS. Mean age was 56.4 (STD 14.4);24% (27/113) were female. Median BMI was 30.3 [IQR 48.5,65.5]. Mean Tidal Volume (Vt) was 430 (STD 54). 64% (72/113) were compliant with low Vt (=<6mL/kg based on IBW). Median PFR 125 [IQR 99,192]. Mortality was 66% (74/113). 44% (50/113) were proned. 62% (70/113) required paralysis. PEEP Index outperformed PFR for discrimination for proning use: AUC 0.73 [95%CI 0.63,0.82], p< 0.005;vs AUC 0.674 [95%CI 0.58,0.77], p= 0.02. PEEP Index performed mildy better than PFR for discrimination of requiring paralytic use in ARDS with AUC 0.68 [95% 0.57,0.78], p< 0.05;vs AUC 0.62 [95%CI 0.51,0.73], p<0.05. APACHE2 score showed poor discrimination for both proning and paralytic use (AUC= 0.46 [95%CI 0.35,0.56];p=0.43 and respectively, AUC=0.45 [95%CI 0.34,0.56];p=0.36). After adjusting for confounders, PEEP Index nor PFR didn’t for predict for mortality (p>0.05);however, our sample was not powered. CONCLUSIONS: PEEP Index (PIx) is a novel tool that can serve as a better discriminatory function to evaluate patients with ARDS in the ICU who will require proning in comparison to traditional used PFR. CLINICAL IMPLICATIONS: PEEP Index (PIx) can serve as an easy alternative calculation to Oxygenation Index (OI) [(FiO2 x PAW) / PaO2] to identify patients that would benefit from early proning and other rescue therapies. Further studies are required to compare and validate PIx and OI prospectively as well as benefit cut-off points between proning and ECMO. DISCLOSURES: No relevant relationships by Perminder Gulani No relevant relationships by Manuel Hache Marliere no disclosure on file for Adarsh Katamreddy;No relevant relationships by Hyomin Lim No relevant relationships by Marzio Napolitano No relevant relationships by Leonidas Palaiodimos No relevant relationships by Anika Sasidharan Nair No relevant relationships by Jee Young You

Donepezil Beyond Alzheimer’s Disease? A Narrative Review of Therapeutic Potentials of Donepezil in Different Diseases

Donepezil hydrochloride is an acetylcholine esterase inhibitor studied and approved to treat Alzheimer’s disease (AD). However, this drug can have positive therapeutic potential in treating different conditions, including various neurodegenerative disorders such as other types of dementia, multiple sclerosis, Parkinson’s disease, psychiatric and mood disorders, and even infectious diseases. Hence, this study reviewed the therapeutic potential of this drug in treating Alzheimer’s and other diseases by reviewing the articles from databases including Web of Science, Scopus, PubMed, Cochrane, and Science Direct. It was shown that donepezil could affect the pathophysiology of these diseases via mechanisms such as increasing the concentration of acetylcholine, modulating local and systemic inflammatory processes, affecting acetylcholine receptors like nicotinic and muscarinic receptors, and activating various cellular signaling via receptors like sigma-1 receptors. Despite many therapeutic potentials, this drug has not yet been approved for treating non-Alzheimer’s diseases, and more comprehensive studies are needed.

Estimating thermodynamic equilibrium solubility and solute-solvent interactions of niclosamide in eight mono-solvents at different temperatures.

Niclosamide is an FDA-approved oral anthelmintic drug currently being repurposed for COVID-19 infection. Its interesting applicability in multiple therapeutic indications has sparked interest in this drug/ scaffold. Despite its therapeutic use for several years, its detailed solubility information from Chemistry Manufacturing & Controls perspective is unavailable. Thus, the present study is intended to determine the mole fraction solubility of niclosamide in commonly used solvents and cosolvents at a temperature range of 298.15-323.15 K. The polymorphic changes from crystalline to monohydrate forms post-equilibration in various solvents were observed. The maximum mole fraction solubility of niclosamide at 323.15 K is 1.103 × 10-3 in PEG400, followed by PEG200 (5.272 × 10-4), 1-butanol (3.047 × 10-4), 2-propanol (2.42 × 10-4), ethanol (1.66 × 10-4), DMSO (1.52 × 10-4), methanol (7.78 × 10-5) and water (3.27 × 10-7). The molecular electrostatic potential showed a linear correlation with the solubility. PEG400 has higher electrostatic potential, and H-bond acceptor count, which forms a hydrogen bond with phenolic -OH of niclosamide and thus enhances its solubility. This data is valuable for the drug discovery and development teams working on the medicinal chemistry and process chemistry of this scaffold.

INFLUENCE OF BUTYRYLCHOLINESTERASE ON THE COURSE OF COVID-19

Butyrylcholinesterase (BChE), a hepatic enzyme produced by the liver is affected by and influences a variety of inflammatory, infectious and metabolic dysfunction processes. Considering that COVID-19 is a multisystem disorder related to conditions influenced by BChE, the potential interrelation of the two is reviewed. BChE is altered in a variety of infectious diseases, and serves as a prognostic marker in both infections and in non-infectious diseases. Closely related to acetylcholinesterase (AChE), BChE plays a role in modulating inflammation via the cholinergic system. It forms part of the signaling pathway linking the immune system, nervous system and the endocrine system. COVID-19 progresses to a stage of unregulated inflammation in a subset of subjects. Cholinergic dysfunction could be potentially responsible for a march to cytokine storm. BChE could influence the course of COVID-19 by acting through the brain-immune-endocrine axis via cholinergic transmission, as well as affecting factors predicting adverse outcomes of COVID-19 (obesity, insulin resistance, coronary artery disease, type 2 diabetes mellitus). Interestingly, variant forms of the enzyme with impaired hydrolytic activity are reported in endogamous ethnic populations. It would be instructive to study the effect of COVID-19 in these natural human knock-out equivalents. Biomed Rev 2021;32: 37-46.

AChEI-EL:Prediction of Acetylcholinesterase Inhibitors Based on Ensemble Learning Model

With the outbreak of the COVID-19, people are eager to develop potential drugs for specific diseases through efficient technological means. Alzheimer's disease (AD) has become one of the top ten causes of death in the world and is a typical neurodegenerative disease. When acetylcholinesterase (AChE) is inhibited, it improves the transmission of cholinergic neurotransmitters in patients and restores cognitive function, so acetylcholinesterase inhibitors (AChEIs) are often considered by researchers as potential drugs for the treatment of AD. Machine learning algorithms and data mining techniques can accelerate drug development and reduce the cost of biological experiments, so it is of great significance to develop models that can accurately predict AChEIs. However, few studies have applied efficient and mature ensemble learning methods to the problem of predicting potential inhibitors of AChE. In this study, we constructed a dataset from a publicly available biological experiment database, and for the first time established an ensemble learning model based on CatBoost and XGBoost to predict potential AChEIs. We demonstrate the advantages of ensemble learning models in building AChEIs predictor based on imbalanced, heterogeneous data through a comprehensive evaluation. Afterwards, we also combined the best-performing models into a blending model AChEI-EL for case studies, and obtained the top-ranked potential inhibitors that have been shown to have the potential to inhibit the AChE. These results suggest that our method has a promising application in the field of AD. Finally, we developed a WEB online prediction platform based on the best model for the use and reference of researchers. © 2022 IEEE.

Disorders of the Cholinergic System in COVID-19 Era-A Review of the Latest Research.

The appearance of the SARS-CoV-2 virus initiated many studies on the effects of the virus on the human body. So far, its negative influence on the functioning of many morphological and physiological units, including the nervous system, has been demonstrated. Consequently, research has been conducted on the changes that SARS-CoV-2 may cause in the cholinergic system. The aim of this study is to review the latest research from the years 2020/2021 regarding disorders in the cholinergic system caused by the SARS-CoV-2 virus. As a result of the research, it was found that the presence of the COVID-19 virus disrupts the activity of the cholinergic system, for example, causing the development of myasthenia gravis or a change in acetylcholine activity. The SARS-CoV-2 spike protein has a sequence similar to neurotoxins, capable of binding nicotinic acetylcholine receptors (nAChR). This may be proof that SARS-CoV-2 can bind nAChR. Nicotine and caffeine have similar structures to antiviral drugs, capable of binding angiotensin-converting enzyme 2 (ACE 2) epitopes that are recognized by SARS-CoV-2, with the potential to inhibit the formation of the ACE 2/SARS-CoV-2 complex. The blocking is enhanced when nicotine and caffeine are used together with antiviral drugs. This is proof that nAChR agonists can be used along with antiviral drugs in COVID-19 therapy. As a result, it is possible to develop COVID-19 therapies that use these compounds to reduce cytokine production. Another promising therapy is non-invasive stimulation of the vagus nerve, which soothes the body's cytokine storm. Research on the influence of COVID-19 on the cholinergic system is an area that should continue to be developed as there is a need for further research. It can be firmly stated that COVID-19 causes a dysregulation of the cholinergic system, which leads to a need for further research, because there are many promising therapies that will prevent the SARS-CoV-2 virus from binding to the nicotinic receptor. There is a need for further research, both in vitro and in vivo. It should be noted that in the functioning of the cholinergic system and its connection with the activity of the COVID-19 virus, there might be many promising dependencies and solutions.

Molecular modeling-guided optimization of acetylcholinesterase reactivators: A proof for reactivation of covalently inhibited targets.

Covalent drugs have been intensively studied in some very important fields such as anti-tumor and anti-virus, including the currently global-spread SARS-CoV-2. However, these drugs may interact with a variety of biological macromolecules and cause serious toxicology, so how to reactivate the inhibited targets seems to be imperative in the near future. Organophosphate was an extreme example, which could form a covalent bound easily with acetylcholinesterase and irreversibly inhibited the enzyme, causing high toxicology. Some nucleophilic oxime reactivators for organophosphate poisoned acetylcholinesterase had been developed, but the reactivation process was still less understanding. Herein, we proposed there should be a pre-reactivated pose during the reactivating process and compounds whose binding pose was easy to transfer to the pre-reactivated pose might be efficient reactivators. Then we refined the previous reactivators based on the molecular dynamic simulation results, the resulting compounds L7R3 and L7R5 were proven as much more efficient reactivators for organophosphate inhibited acetylcholinesterase than currently used oximes. This work might provide some insights for constructing reactivators of covalently inhibited targets by using computational methods.

Efficacy of Silene arenosa extract on acetylcholinesterase in Bungarus sindanus (krait) venom.

OBJECTIVE: To examine the efficacy of Silene arenosa extract on acetylcholinesterase (AChE) of krait (Bungarus Sindanus) snake venom. METHODS: The present project designed to evaluate the inhibition of AChE by following standard procedures. RESULTS: Statistical analysis of the results showed that Silene arenosa exerted 73% inhibition against the krait venom acetylcholinesterase at fixed substrate acetylcholine (ACh) concentration (0.5 mM). Kinetic analysis using the Lineweaver Burk plot revealed that Silene arenosa caused a competitive type of inhibition i.e. Km values increased from 26.6 to 93.3 mM (26.6% to 93.3%) and Vmax remained constant in a concentration-dependent manner. Silene arenosa competes with the substrate to bind at the active site of the enzyme. The Kmapp of venom AChE for Silene arenosa increased from 60% to 81.6% and the Vmaxapp remains constant. Ki (inhibition constant was estimated to be 48 µg for snake venom; while the Km (Michaelis-Menten constant of AChE- substrate into AChE and product) was estimated to be 0.5 mM. The IC50 of AchE calculated for Silene arenosa was 67 µg. CONCLUSION: The present results suggest that Silene arenosa extract can be considered as an inhibitor of snake venom AChE.

Toxicological insights of Spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?

The Spike protein (S protein) is a critical component in the infection of the new coronavirus (SARS-CoV-2). The objective of this work was to evaluate whether peptides from S protein could cause negative impact in the aquatic animals. The aquatic toxicity of SARS-CoV-2 Spike protein peptides derivatives has been evaluated in tadpoles (n = 50 tadpoles/5 replicates of 10 animals) from species Physalaemus cuvieri (Leptodactylidae). After synthesis, purification, and characterization of peptides (PSDP2001, PSDP2002, PSDP2003) an aquatic contamination has been simulated with these peptides during 24 h of exposure in two concentrations (100 and 500 ng/mL). The control group ("C") was composed of tadpoles kept in polyethylene containers containing de-chlorinated water. Oxidative stress, antioxidant biomarkers and AChE activity were assessed. In both concentrations, PSPD2002 and PSPD2003 increased catalase and superoxide dismutase antioxidants enzymes activities, as well as oxidative stress (nitrite levels, hydrogen peroxide and reactive oxygen species). All three peptides also increased acetylcholinesterase activity in the highest concentration. These peptides showed molecular interactions in silico with acetylcholinesterase and antioxidant enzymes. Aquatic particle contamination of SARS-CoV-2 has cholinesterasic effect in P. cuvieri tadpoles. These findings indicate that the COVID-19 can constitute environmental impact or biological damage potential.